title: p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway.
abstract: Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAM domain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.
authors.affiliation: Unité de Régulation des Infections Rétrovirales, Institut Pasteur, 75015 Paris, France.
authors.forename: Awatef
authors.initials: A
authors.lastname: Allouch
authors.forename: Annie
authors.initials: A
authors.lastname: David
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Amie
authors.forename: Hichem
authors.initials: H
authors.lastname: Lahouassa
authors.forename: Loïc
authors.initials: L
authors.lastname: Chartier
authors.forename: Florence
authors.initials: F
authors.lastname: Margottin-Goguet
authors.forename: Françoise
authors.initials: F
authors.lastname: Barré-Sinoussi
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.forename: Asier
authors.initials: A
authors.lastname: Sáez-Cirión
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pancino
mesh_terms: D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics; D003854:Deoxyribonucleotides / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015658:HIV Infections / Q000378:metabolism* / Q000628:therapy / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000096:biosynthesis* / Q000235:genetics; D000076106:SAM Domain and HD Domain-Containing Protein 1; D015302:Simian Immunodeficiency Virus / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics; D014779:Virus Replication / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018076:DNA, Complementary; D004279:DNA, Viral; D003854:Deoxyribonucleotides; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012264:Ribonucleotide Reductases; C108427:ribonucleotide reductase R2 subunit; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins